Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors

ABSTRACT

The present invention relates to novel compounds, in particular novel indole and benzomorpholine derivatives according to Formula (I) wherein all radicals are as defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions as well as to the use of such compounds or compositions for the prevention and treatment of such diseases in which mGluR2 is involved.

IN THE CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to European Application No. 08166832.9,filed Oct. 16, 2008, which is hereby incorporated herein by reference inits entirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to novel indole and benzomorpholinederivatives which are positive allosteric modulators of the metabotropicglutamate receptor subtype 2 (“mGluR2”) and which are useful for thetreatment or prevention of neurological and psychiatric disordersassociated with glutamate dysfunction and diseases in which the mGluR2subtype of metabotropic receptors is involved. The invention is alsodirected to pharmaceutical compositions comprising such compounds, toprocesses to prepare such compounds and compositions, and to the use ofsuch compounds for the prevention or treatment of neurological andpsychiatric disorders and diseases in which mGluR2 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system. Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function. Furthermore,glutamate is at the centre of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptors channels (iGluRs), and the NMDA, AMPA andkainate receptors which are responsible for fast excitatorytransmission.

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor, which results in the activation of the G-protein andintracellular signaling pathways.

The mGluR2 subtype is negatively coupled to adenylate cyclase viaactivation of Gαi-protein, and its activation leads to inhibition ofglutamate release in the synapse. In the central nervous system (CNS),mGluR2 receptors are abundant mainly throughout cortex, thalamicregions, accessory olfactory bulb, hippocampus, amygdala,caudate-putamen and nucleus accumbens.

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders. In addition, activating mGluR2 in variousanimal models was shown to be efficacious, thus representing a potentialnovel therapeutic approach for the treatment of schizophrenia, epilepsy,addiction/drug dependence, Parkinson's disease, pain, sleep disordersand Huntington's disease.

To date, most of the available pharmacological tools targeting mGluRsare orthosteric ligands which activate several members of the family asthey are structural analogs of glutamate.

A new avenue for developing selective compounds acting at mGluRs is toidentify compounds that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. Variouscompounds have been described as mGluR2 positive allosteric modulators.WO2007/104783 and WO2006/030032 (Addex & Janssen Pharmaceutica) describerespectively 3-cyano-pyridinone and pyridinone derivatives as mGluR2positive allosteric modulators. None of the specifically disclosedcompounds therein are structurally related to the compounds of thepresent invention.

It was demonstrated that such compounds do not activate the receptor bythemselves. Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate, which by itself induces aminimal response. Mutational analysis has demonstrated unequivocallythat the binding of mGluR2 positive allosteric modulators does not occurat the orthosteric site, but instead at an allosteric site situatedwithin the seven transmembrane region of the receptor.

Animal data are suggesting that positive allosteric modulators of mGluR2have effects in anxiety and psychosis models similar to those obtainedwith orthosteric agonists. Allosteric modulators of mGluR2 were shown tobe active in fear-potentiated startle, and in stress-inducedhyperthermia models of anxiety. Furthermore, such compounds were shownto be active in reversal of ketamine- or amphetamine-inducedhyperlocomotion, and in reversal of amphetamine-induced disruption ofprepulse inhibition of the acoustic startle effect models ofschizophrenia (J. Pharmacol. Exp. Ther. 2006, 318, 173-185;Psychopharmacology 2005, 179, 271-283).

Recent animal studies further reveal that the selective positiveallosteric modulator of metabotropic glutamate receptor subtype 2biphenyl-indanone (BINA) blocks a hallucinogenic drug model ofpsychosis, supporting the strategy of targeting mGluR2 receptors fortreating glutamatergic dysfunction in schizophrenia (Mol. Pharmacol.2007, 72, 477-484).

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 or DCG-IV. These dataprovide evidence for yet another novel therapeutic approach to treatabove mentioned neurological and psychiatric diseases involving mGluR2,which would use a combination of a positive allosteric modulator ofmGluR2 together with an orthosteric agonist of mGluR2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having metabotropic glutamatereceptor 2 modulator activity, said compounds having the Formula (I)

and the stereochemically isomeric forms thereof, wherein

-   R¹ is C₁₋₆alkyl; or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl, halo,    phenyl, or phenyl substituted with halo, trifluoromethyl or    trifluoromethoxy;-   R² is halo, trifluoromethyl, C₁₋₃alkyl or cyclopropyl;-   R³ is hydrogen, halo or trifluoromethyl;-   n is 1 or 2;-   X is —CH₂CH₂—O, —CH═CH—, or —CH₂CH₂—;-   Y is —O— or —CR⁴(OH)—;-   R⁴ is hydrogen or C₁₋₃alkyl;    and the pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

-   R¹ is C₁₋₆alkyl; or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl,    phenyl, or phenyl substituted with halo, trifluoromethyl or    trifluoromethoxy;-   R² is halo, trifluoromethyl, C₁₋₃alkyl or cyclopropyl;-   R³ is hydrogen, halo or trifluoromethyl;-   n is 1 or 2;-   X is —CH₂CH₂—O, —CH═CH—, or —CH₂CH₂—;-   Y is —O— or —CR⁴(OH)—;-   R⁴ is hydrogen or C₁₋₃alkyl;    and the pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

-   R¹ is C₁₋₆alkyl; or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl or    phenyl-   R² is halo, trifluoromethyl or cyclopropyl;-   R³ is hydrogen, halo or trifluoromethyl;-   n is 2;-   X is —CH₂CH₂—O— or —CH═CH—;-   Y is —O— or —CR⁴(OH)—;-   R⁴ is hydrogen or C₁₋₃alkyl;    and the pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

-   R¹ is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl,    (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;-   R² is chloro, bromo, cyclopropyl or trifluoromethyl;-   R³ is hydrogen, chloro or trifluoromethyl;-   n is 2;-   X is —CH₂CH₂—O— or —CH═CH—;-   Y is —O— or —CR⁴(OH)—;-   R⁴ is hydrogen or C₁₋₃alkyl;    or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the invention relates to a compound according toFormula (I) or a stereochemically isomeric form thereof, wherein

-   R¹ is 1-butyl, 3-methyl-1-butyl or (cyclopropyl)methyl;-   R² is chloro;-   R³ is hydrogen;-   n is 2;-   X is —CH₂CH₂—O— or —CH═CH—;-   Y is —O— or —CR⁴(OH)—;-   R⁴ is hydrogen or methyl;    or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment of the present invention, interesting compounds ofFormula (I) and the stereoisomeric forms thereof are selected from thegroup comprising

-   1-Butyl-3-chloro-4-[4-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-1H-pyridin-2-one    (E1),-   trans-1-Butyl-3-chloro-4-[4-(4-hydroxy-cyclohexyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-1H-pyridin-2-one    (E2),-   trans-1-Butyl-3-chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E3),-   cis-1-Butyl-3-chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E4),-   trans-1-Butyl-3-chloro-4-[1-(4-hydroxy-4-methyl-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E5),-   cis-1-Butyl-3-chloro-4-[1-(4-hydroxy-4-methyl-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E6),-   trans-3-Chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1-(3-methyl-butyl)-1H-pyridin-2-one    (E7),-   trans-3-Chloro-1-cyclopropylmethyl-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E8),-   1-Butyl-3-chloro-4-[1-(tetrahydro-pyran-4-yl)-1H-indol-5-yl]-1H-pyridin-2-one    (E9),    and the pharmaceutically acceptable addition salts and solvates    thereof.

In an embodiment of the present invention, preferably said compound ofFormula (I) is

-   trans-1-Butyl-3-chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E3) or-   trans-1-Butyl-3-chloro-4-[1-(4-hydroxy-4-methyl-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one    (E5).

Whenever the term “substituted” is used in the present invention, it ismeant to indicate that one or more hydrogens, preferably from 1 to 3hydrogens, more preferably 1 hydrogen, on the atom or radical indicatedin the expression using “substituted” are replaced with a selection fromthe indicated group, provided that the normal valency is not exceeded,and that the substitution results in a chemically stable compound, i.e.a compound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into atherapeutic agent. For example, when phenyl is substituted with halo,this means that said phenyl is substituted with one or more substituentsselected from halo.

The notation C₁₋₃alkyl as a group or part of a group defines asaturated, straight or branched, hydrocarbon radical having from 1 to 3carbon atoms such as, for example, methyl, ethyl, 1-propyl and1-methylethyl.

The notation C₁₋₆alkyl as a group or part of a group defines asaturated, straight or branched, hydrocarbon radical having from 1 to 6carbon atoms such as, for example, methyl, ethyl, 1-propyl,1-methylethyl, 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, 1-pentyl,1-hexyl and the like.

The notation C₃₋₇cycloalkyl defines a saturated, cyclic hydrocarbonradical having from 3 to 7 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The notation halo or halogen as a group or part of a group is genericfor fluoro, chloro, bromo, iodo.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.

The pharmaceutically acceptable salts are defined to comprise thetherapeutically active non-toxic acid addition salt forms that thecompounds according to Formula (I) are able to form. Said salts can beobtained by treating the base form of the compounds according to Formula(I) with appropriate acids, for example inorganic acids, for examplehydrohalic acid, in particular hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid and phosphoric acid; organic acids, forexample acetic acid, hydroxyacetic acid, propanoic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

Conversely said salt forms can be converted into the free base form bytreatment with an appropriate base.

The compounds according to Formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic base saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkaline and earth alkaline metal salts, in particular lithium,sodium, potassium, magnesium and calcium salts, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, andsalts with amino acids, for example arginine and lysine.

Conversely, said salt forms can be converted into the free acid forms bytreatment with an appropriate acid.

The term solvate comprises the solvent addition forms as well as thesalts thereof, which the compounds of formula (I) are able to form.Examples of such solvent addition forms are e.g. hydrates, alcoholatesand the like.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of Formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. Theinvention also embraces each of the individual isomeric forms of thecompounds of Formula (I) and their salts and solvates, substantiallyfree, i.e. associated with less than 10%, preferably less than 5%, inparticular less than 2% and most preferably less than 1% of the otherisomers. Thus, when a compound of formula (I) is for instance specifiedas (R), this means that the compound is substantially free of the (S)isomer. Stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a compound, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the compound has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S-[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α”, if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ³H, ¹¹C,¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, theradioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

A compound according to the invention therefore inherently comprises acompound with one or more isotopes of one or more elements, and mixturesthereof, including a radioactive compound, also called radiolabelledcompound, wherein one or more non-radioactive atoms has been replaced byone of its radioactive isotopes. By the term “radiolabelled compound” ismeant any compound according to formula (I), or a pharmaceuticallyacceptable salt thereof, which contains at least one radioactive atom.For example, a compound can be labelled with positron or with gammaemitting radioactive isotopes. For radioligand-binding techniques, the³H-atom or the ¹²⁵I-atom is the atom of choice to be replaced. Forimaging, the most commonly used positron emitting (PET) radioactiveisotopes are ¹¹C, ¹⁸F, ¹⁵O and ¹³N, all of which are acceleratorproduced and have half-lives of 20, 100, 2 and 10 minutes (min)respectively. Since the half-lives of these radioactive isotopes are soshort, it is only feasible to use them at institutions which have anaccelerator on site for their production, thus limiting their use. Themost widely used of these are ¹⁸F, ^(99m)Tc, ²⁰¹Tl and ¹²³I. Thehandling of these radioactive isotopes, their production, isolation andincorporation in a molecule are known to the skilled person.

In particular, the radioactive atom is selected from the group ofhydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular,the radioactive isotope is selected from the group of ³H, ¹¹C, ¹⁸F,¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.

In an embodiment, radiolabelled compounds of the present invention maybe used as positron emission tomography (PET) radioligands for imagingthe metabotropic glutamate receptor subtype 2 (mGluR2). Radionuclidestypically used in PET are, for example, ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, inparticular ¹⁸F.

As used in the specification and the appended claims, the singular forms“a”, “an,” and “the” also include plural referents unless the contextclearly dictates otherwise. For example, “a compound” means 1 compoundor more than 1 compound.

The terms described above and others used in the specification are wellunderstood to those in the art.

PREPARATION

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person. Inparticular, the compounds can be prepared according to the followingsynthesis methods.

The compounds of Formula (I) may be synthesized in the form of racemicmixtures of enantiomers which can be separated from one anotherfollowing art-known resolution procedures. The racemic compounds ofFormula (I) may be converted into the corresponding diastereomeric saltforms by reaction with a suitable chiral acid. Said diastereomeric saltforms are subsequently separated, for example, by selective orfractional crystallization and the enantiomers are liberated therefromby alkali. An alternative manner of separating the enantiomeric forms ofthe compounds of Formula (I) involves liquid chromatography using achiral stationary phase. Said pure stereochemically isomeric forms mayalso be derived from the corresponding pure stereochemically isomericforms of the appropriate starting materials, provided that the reactionoccurs stereospecifically.

A. Preparation of the Final Compounds Experimental Procedure 1

The compounds according to Formula (I) can be prepared by reacting anintermediate of Formula (II) with an intermediate of Formula (III)according to reaction scheme 1 wherein Z is a group suitable for Pdmediated coupling with boronic acids or boronic esters such as, forexample, a halogen or triflate, and R⁵ and R⁶ may be hydrogen or alkyl,for example C₁₋₆alkyl, or may be taken together to form, for example,the bivalent radical of formula —CH₂CH₂—, —CH₂CH₂CH₂—, or—C(CH₃)₂C(CH₃)₂; and wherein all other variables are defined as inFormula (I). The reaction may be performed in a suitable reaction-inertsolvent such as, for example, 1,4-dioxane or a mixture of inert solventssuch as, for example, 1,4-dioxane/N,N-dimethylformamide (DMF). Thereaction can be performed in the presence of a suitable base such as,for example, aqueous NaHCO₃ or aqueous Na₂CO₃. The reaction mayconveniently be carried out in the presence of a Pd-complex catalystsuch as, for example, tetrakis(triphenylphosphine)palladium(0). Thereaction mixture may be heated for a suitable period of time to allowthe completion of the reaction, either under traditional heating orunder microwave irradiation.

Experimental Procedure 2

The compounds according to Formula (I) wherein Y is —CH(OH)—, herebynamed (I-a), can also be prepared by reacting an intermediate of Formula(IV) under reductive conditions that are known by those skilled in theart. The reaction is illustrated in reaction scheme 2 wherein allsubstituents are defined as mentioned before. The reaction can becarried out in the presence of, for example, sodium borohydride, in asuitable solvent such as, for example, methanol. The reaction may beperformed at a suitable temperature, typically room temperature, for asuitable period of time that allows the completion of the reaction.

Experimental Procedure 3

The compounds according to Formula (I) wherein Y is —C(C₁₋₃alkyl)(OH)—,hereby named (I-b), can be prepared by art known procedures by reactingan intermediate of Formula (IV) with a suitable C₁₋₃alkyl source suchas, for example, C₁₋₃alkylmagnesium bromide or C₁₋₃alkyllithium. Thisreaction is shown in reaction scheme 3 wherein halide is a suitablehalogen such as, for example, bromo and all other substituents aredefined as mentioned before. The reaction can be carried out in an inertsolvent such as, for example, tetrahydrofuran (THF), diethyl ether ordioxane. Typically, the mixture can be stirred for 1 to 48 hours at atemperature between 0-100° C.

B. Preparation of the Intermediates Experimental Procedure 4

Intermediates of Formula (II) wherein Z is triflate, hereby named(II-a), can be prepared by reacting an intermediate of Formula (V) withtriflic anhydride (also called trifluoromethanesulfonic anhydride)according to reaction scheme 4 wherein all variables are defined as inFormula (I). The reaction can be performed in a suitable reaction-inertsolvent such as, for example, dichloromethane (DCM). The reaction may beperformed in the presence of a base such as, for example, pyridine. Thereaction may conveniently be carried out at a low temperature such as,for example, −78° C.

Experimental Procedure 5

Intermediates of Formula (V) wherein R² is restricted to R^(2a) (halo),hereby called Formula (V-a), can be prepared by reacting an intermediateof Formula (VI) with a N-halosuccinimide reagent, such asN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide, accordingto reaction scheme 5 wherein R^(2a) is defined as halo and wherein allother variables are defined as in Formula (I). This reaction can beperformed in a suitable reaction-inert and aprotic solvent such as, forexample, DCM or 1,2-dichloroethane (DCE). The reaction mixture can bestirred at a suitable temperature, typically at room temperature, forthe required time to achieve completion of the reaction.

Experimental Procedure 6

Intermediates of Formula (V) wherein R² is restricted to R^(2b)(trifluoromethyl, C₁₋₃alkyl or cyclopropyl), hereby named (V-b), can beprepared by hydrogenation of intermediates of Formula (VII) according toreaction scheme 6 wherein R^(2b) is trifluoromethyl, C₁₋₃alkyl orcyclopropyl and wherein all other variables are defined as in Formula(I). The reaction may be performed in a suitable reaction-inert solventsuch as, for example, ethanol. The reaction can be performed in thepresence of a catalyst such as, for example, 10% palladium on activatedcarbon, for a period of time that ensures the completion of thereaction. The reaction typically can be carried out at room temperatureand 1 atmosphere of hydrogen for 2 hours.

Experimental Procedure 7

Intermediates of Formula (VI) can be prepared by hydrogenolysis ofintermediates of Formula (VIII) according to reaction scheme 7 whereinall variables are defined as in Formula (I). This reaction can beperformed in a suitable reaction-inert solvent such as, for example,ethanol. The reaction may be carried out in the presence of a catalystsuch as, for example, 10% palladium on activated carbon, for a period oftime that ensures the completion of the reaction. The reaction typicallycan be performed at room temperature and 1 atmosphere of hydrogen for 2hours.

Experimental Procedure 8

Intermediates of Formula (VIII) can be prepared by art known proceduresby reacting commercially available 4-benzyloxy-1H-pyridin-2-one with acommercially available alkylating agent of Formula (IX) according toreaction scheme 8 in which Q is a suitable leaving group such as, forexample, a halogen, and wherein R¹ is defined as in Formula (I). Thereaction typically is performed using a base such as, for example,K₂CO₃, and optionally in the presence of a iodine salt such as, forexample, KI. The reaction can be carried out in an inert solvent suchas, for example, CH₃CN or DMF. The reaction may conveniently be carriedout a moderately high temperature such as, for example, 80-120° C., fora suitable period of time that allows the completion of the reaction,for example 16 hours.

Experimental Procedure 9

Intermediates of Formula (VII) wherein R^(2b) is restricted to R^(2c)(CF₃), hereby named (VII-b), can be prepared by reacting an intermediateof Formula (VII-a) wherein halo is restricted to iodine, hereby named(VII-a1), with commercially available methyl2,2-difluoro-2-(fluorosulfonyl)acetate according to reaction scheme 9wherein R^(2c) is CF₃ and wherein R¹ is defined as in Formula (I). Thereaction can be performed in a suitable reaction-inert solvent such as,for example, DMF. The reaction may be carried out in the presence of asuitable copper salt such as, for example, copper(I) iodide. Heating canbe applied for a suitable period of time to allow the completion of thereaction, for example, at 100° C. for 5 hours.

Experimental Procedure 10

Intermediates of Formula (VII) wherein R² is restricted to R^(2c)(C₁₋₃alkyl or cyclopropyl), hereby named (VII-c), can be prepared byreacting an intermediate of Formula (VII-a) with a C₁₋₃alkyl- orcyclopropyl-boronic acid derivative such as, for example,cyclopropylboronic acid or methylboronic acid according to reactionscheme 10 wherein R^(2c) is defined as C₁₋₃alkyl or cyclopropyl andwherein all other variables are defined as in Formula (I). The reactionmay be performed in a suitable reaction-inert solvent such as, forexample, 1,4-dioxane. The reaction can be carried out in the presence ofa suitable palladium catalyst-complex such as, for example, a[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-DCMcomplex. The reaction can be performed in the presence of a suitablebase such as, for example, NaHCO₃. Heating can be applied for a suitableperiod of time to allow the completion of the reaction, for example at175° C. for 20 minutes under microwave irradiation.

Experimental Procedure 11

Intermediates of Formula (VII-a) can be prepared by reacting anintermediate of Formula (VIII) with a commercially availableN-halosuccinimide such as, for example, N-chloro- (NCS), N-bromo- (NBS)or N-iodosuccinimide (NIS) as is illustrated in reaction scheme 11wherein all variables are defined as mentioned before. The reaction canbe performed in a suitable reaction-inert solvent such as, for example,DMF, DCM or acetic acid. The reaction may typically be carried out atroom temperature for 1 to 24 hours.

Experimental Procedure 12

Intermediates of Formula (III) can be prepared by art known proceduresby reacting an intermediate of Formula (X) with a suitable boron sourcesuch as, for example, bis(pinacolato)diboron as is shown in reactionscheme 12 wherein all variables are defined as in Formula (I). Thereaction can be performed in the presence of a palladium catalyst suchas, for example,1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride in an inertsolvent such as, for example, DCM. The reaction may be carried out inthe presence of a suitable salt such as, for example, potassium acetateat a moderately high temperature such as, for example, 110° C. during,for example, 16 hours.

Additionally, intermediates of Formula (III) can be prepared by artknown procedures of metal-halogen exchange and subsequent reaction withan appropriate boron source from intermediates of Formula (X). This typeof reaction can be carried out by using, for example, an intermediate ofFormula (X) and an organolithium compound such as, for example,n-butyllithium. The reaction can be performed at a moderately lowtemperature such as, for example, −40° C. in an inert solvent such as,for example, THF. This reaction is followed by subsequent reaction withan appropriate boron source such as, for example, trimethoxyborane.

In reaction scheme (12), R⁵ and R⁶ are defined as mentioned before, halois a suitable halogen such as, for example, bromo and all othervariables are defined as in Formula (I).

Intermediates of Formula (X) wherein Y is —O—, can be prepared accordingto experimental procedure 17 and experimental procedure 18.

Experimental Procedure 13

Intermediates of Formula (X) wherein Y is —C(C₁₋₃alkyl)(OH)—, herebynamed (X-a), can be prepared by art known procedures by reacting anintermediate of Formula (XI) with a suitable C₁₋₃alkyl source such as,for example, C₁₋₃alkylmagnesium bromide or C₁₋₃alkyllithium. Thisreaction is shown in reaction scheme 13 wherein halo is a suitablehalogen such as, for example, bromo and all other substituents aredefined as mentioned before. The reaction can be carried out in an inertsolvent such as, for example, THF, diethyl ether or dioxane. Typically,the mixture can be stirred for 1 to 48 hours at a temperature between0-100° C.

Experimental Procedure 14

Intermediates of Formula (X) wherein Y is —CH(OH)—, hereby named (X-b),can be prepared by reacting an intermediate of Formula (XI) underreductive conditions that are known by those skilled in the art. Thereaction is illustrated in reaction scheme 14 wherein all substituentsare defined as mentioned before. The reaction can be carried out in thepresence of, for example, sodium borohydride in a suitable solvent suchas, for example, methanol. The reaction may be performed at a suitabletemperature, typically room temperature, for a suitable period of timethat allows the completion of the reaction.

Experimental Procedure 15

Intermediates of Formula (IV) can be prepared by reacting anintermediate of Formula (III) wherein Y is restricted to —CH(OH)—,hereby named (III-a), with an intermediate of Formula (II), according toreaction scheme 15 wherein Z is a group suitable for Pd mediatedcoupling with boronic acids or boronic esters such as, for example, ahalogen or triflate, R⁵ and R⁶ may be hydrogen or alkyl, or may be takentogether to form for example the bivalent radical of formula —CH₂CH₂—,—CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂— and all other variables are defined asmentioned before. The reaction can be performed in a suitablereaction-inert solvent, such as, for example, 1,4-dioxane or in amixture of inert solvents such as, for example, 1,4-dioxane/DMF. Thereaction may be carried out in the presence of a suitable base such as,for example, aqueous NaHCO₃ or aqueous Na₂CO₃. The reaction can beperformed using a Pd-complex catalyst such as, for example,tetrakis(triphenylphosphine)palladium(0). Usually, the reaction mixtureis heated for a suitable period of time to allow the completion of thereaction either under traditional heating or under microwaveirradiation.

Experimental Procedure 16

Intermediates of Formula (XI) can be prepared by subjecting anintermediate of Formula (XII) to acidic conditions that are known bythose skilled in the art. This reaction is illustrated in reactionscheme 16 wherein all variables are defined as mentioned before. Thereaction can be performed in the presence of an acid such as, forexample, p-toluenesulfonic acid. The reaction can be performed in asuitable reaction solvent such as, for example, acetone. The reactionmay conveniently be carried out under microwave irradiation at asuitable temperature, typically at 100° C., for a suitable period oftime that allows the completion of the reaction.

Intermediates of Formula (XII) can be prepared according to experimentalprocedure 17 and experimental procedure 18.

Experimental Procedure 17

Intermediates of Formula (XIII) can be prepared by reacting thecommercially available intermediate of Formula (XV) with a tosylatederivative of Formula (XIV) according to reaction scheme 17 wherein W is—O— or

according to reaction scheme 17 wherein halo is a suitable halogen suchas, for example, bromo, Ts means tosylate and all other variables aredefined as in Formula (I).

The intermediate of Formula (XIV) wherein W=—O— and n=1 is commerciallyavailable (CAS [13694-84-3]); W=—O— and n=2 (CAS [97986-34-0]) can beprepared according to the synthetic procedure described in WO 2007148648A1;

n=2 (CAS [23511-05-9]) can be prepared according to the syntheticprocedure described in J. Chem. Soc., Perkin Trans. 1, 2002, 2251-2255;and

n=1 can be prepared in analogy to the synthetic procedure described inJ. Chem. Soc., Perkin Trans. 1, 2002, 2251-2255 but starting from1,4-dioxaspiro[4.4]nonan-7-ol. The reaction according to reaction scheme17 can be carried out under alkylation conditions that are known bythose skilled in the art such as, for example, in the presence of basesuch as, for example, potassium hydroxide in a suitable reaction solventsuch as, for example, dimethylsulphoxide. The reaction may be performedat a suitable temperature, typically at 60° C., for a suitable period oftime that allows the completion of the reaction.

Experimental Procedure 18

Intermediates of Formula (XVI), can be prepared by reacting thecommercially available 1,2-dibromoethane with an aminophenol derivativeof Formula (XVII) under alkylation conditions as is illustrated inreaction scheme 18, wherein all variables are defined as in Formula (I)and experimental procedure 17. Such alkylation conditions are known bythose skilled in the art, such as for example, in the presence of a basesuch as for example K₂CO₃ in a suitable reaction solvent such as, forexample, DMF. The reaction may be carried out under microwaveirradiation at a suitable temperature, typically 180° C., for a suitableperiod of time that allows the completion of the reaction.

Experimental Procedure 19

Intermediates of Formula (XVII) can be prepared by reacting anintermediate of Formula (XVIII) with a commercially availableN-halosuccinimide such as N-chloro-(NCS), N-bromo- (NBS) orN-iodosuccinimide (NIS) according to reaction scheme 19 wherein allvariables are defined as in Formula (I) and experimental procedure 17.This reaction can be performed in a suitable reaction-inert solvent suchas, for example, DMF, DCM or acetic acid. The reaction typically can becarried out at room temperature for 1 to 24 hours.

Experimental Procedure 20

Intermediates of Formula (XVIII) can be prepared by reacting anintermediate of Formula (XX) with a cyclic ketone derivative of Formula(XIX) under reductive amination conditions that are known by thoseskilled in the art. This is illustrated in reaction scheme 20 whereinall variables are defined as in mentioned hereabove. The reaction may beperformed, for example, in the presence of triacetoxy borohydride in asuitable reaction-inert solvent such as, for example, DCE, at a suitabletemperature, typically at room temperature, for a suitable period oftime that allows the completion of the reaction.

Intermediates of Formula (XIX) are commercially available or can beprepared by those skilled in the art.

The intermediate of Formula (XX) wherein R³ is Cl, can be preparedaccording to the synthetic procedure described in Journal of theChemical Society (1963), (November), 5571-2. The intermediate of Formula(XX) wherein R³ is H is commercially available.

Pharmacology

The compounds provided in this invention are positive allostericmodulators of metabotropic glutamate receptors, in particular they arepositive allosteric modulators of mGluR2. The compounds of the presentinvention do not appear to bind to the glutamate recognition site, theorthosteric ligand site, but instead to an allosteric site within theseven transmembrane region of the receptor. In the presence of glutamateor an agonist of mGluR2, the compounds of this invention increase themGluR2 response. The compounds provided in this invention are expectedto have their effect at mGluR2 by virtue of their ability to increasethe response of such receptors to glutamate or mGluR2 agonists,enhancing the response of the receptor. Hence, the present inventionrelates to a compound according to the present invention for use as amedicament. The present invention also relates to a compound accordingto the invention or a pharmaceutical composition according to theinvention for use in the treatment or prevention, in particulartreatment, of a disease or a condition in a mammal, including a human,the treatment or prevention of which is affected or facilitated by theneuromodulatory effect of allosteric modulators of mGluR2, in particularpositive allosteric modulators thereof. The present invention alsorelates to the use of a compound according to the invention or apharmaceutical composition according to the invention for themanufacture of a medicament for treating or preventing, in particulartreating, a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of allosteric modulators of mGluR2, in particular positiveallosteric modulators thereof. The present invention also relates to acompound according to the present invention or a pharmaceuticalcomposition according to the invention for use in the manufacture of amedicament for treating or preventing, in particular treating, acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect ofallosteric modulators of mGluR2, in particular positive allostericmodulators thereof. The present invention also relates to a compoundaccording to the present invention or a pharmaceutical compositionaccording to the invention for treating or preventing, in particulartreating, a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of allosteric modulators of mGluR2, in particular positiveallosteric modulators thereof.

Also, the present invention relates to the use of a compound accordingto the invention or a pharmaceutical composition according to theinvention for the manufacture of a medicament for treating, preventing,ameliorating, controlling or reducing the risk of various neurologicaland psychiatric disorders associated with glutamate dysfunction in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of positiveallosteric modulators of mGluR2.

Where the invention is said to relate to the use of a compound orcomposition according to the invention for the manufacture of amedicament for e.g. the treatment of a mammal, it is understood thatsuch use is to be interpreted in certain jurisdictions as a method ofe.g. treatment of a mammal, comprising administering to a mammal in needof such e.g. treatment, an effective amount of a compound or compositionaccording to the invention.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancetolerance, substance withdrawal (including substances such as, forexample, opiates, nicotine, tobacco products, alcohol, benzodiazepines,cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic states, severe pain, intractable pain, neuropathicpain, and post-traumatic pain), tardive dyskinesia, sleep disorders(including narcolepsy), attention deficit/hyperactivity disorder, andconduct disorder.

In particular, the condition or disease is a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder,selected from the group of agoraphobia, generalized anxiety disorder(GAD), obsessive-compulsive disorder (OCD), panic disorder,posttraumatic stress disorder (PTSD), social phobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorderselected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder

Preferably, the central nervous system disorder is a personalitydisorder selected from the group of obsessive-compulsive personalitydisorder, schizoid personality disorder, and schizotypal personalitydisorder.

Preferably, the central nervous system disorder is a substance-relateddisorder selected from the group of alcohol abuse, alcohol dependence,alcohol withdrawal, alcohol withdrawal delirium, alcohol-inducedpsychotic disorder, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, nicotine dependence, nicotinewithdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder andsubstance-induced mood disorder.

Preferably, the central nervous system disorder is migraine.

Preferably, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy.

Preferably, the central nervous system disorder isattention-deficit/hyperactivity disorder.

Preferably, the central nervous system disorder is a cognitive disorderselected from the group of delirium, substance-induced persistingdelirium, dementia, dementia due to HIV disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type, substance-induced persisting dementia and mildcognitive impairment.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Because such positive allosteric modulators of mGluR2, includingcompounds of Formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds ofFormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of Formula (I), incombination with an mGluR2 agonist.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to Formula (I), apharmaceutically acceptable salt thereof, a solvate thereof or astereochemically isomeric form thereof.

The invention also relates to a pharmaceutical composition comprising atherapeutically effective amount of a compound according to Formula (I)and a pharmaceutically acceptable carrier or excipient.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof, or anysubgroup or combination thereof may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, foradministration orally, rectally, percutaneously, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations that areintended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs in the treatment, prevention, control, amelioration,or reduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility as well as to the use ofsuch a composition for the manufacture of a medicament. The presentinvention also relates to a combination of a compound according to thepresent invention and a mGluR2 orthosteric agonist. The presentinvention also relates to such a combination for use as a medicament.The present invention also relates to a product comprising (a) acompound according to the present invention, a pharmaceuticallyacceptable salt thereof or a solvate thereof, and (b) a mGluR2orthosteric agonist, as a combined preparation for simultaneous,separate or sequential use in the treatment or prevention of a conditionin a mammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of mGluR2allosteric modulators, in particular positive mGluR2 allostericmodulators. The present invention also relates to a compound accordingto the invention in combination with an orthosteric agonist of mGluR2for use in the treatment or prevention of the above mentioned diseasesor conditions. The different drugs of such a combination or product maybe combined in a single preparation together with pharmaceuticallyacceptable carriers or diluents, or they may each be present in aseparate preparation together with pharmaceutically acceptable carriersor diluents.

The present invention also relates to a compound according to theinvention and an orthosteric agonist of mGluR2 as a combined preparationfor simultaneous, separate or sequential use in the treatment orprevention of the above mentioned diseases or conditions.

The following examples are intended to illustrate but not to limit thescope of the present invention.

Chemistry

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification.

Hereinafter, “THF” means tetrahydrofuran; “DMF” meansN,N-dimethylformamide; “EtOAc” means ethyl acetate; “DCM” meansdichloromethane; “DME” means 1,2-dimethoxyethane; “DCE” means1,2-dichloroethane; “DIPE” means diisopropylether; “DMSO” meansdimethylsulfoxide; “DBU” means 1,8-diaza-7-bicyclo[5.4.0]undecene,“MeOH” means methanol, “h.” means hour(s), “s.” means second(s), “min.”means minute(s), “r.t.” means room temperature, “M.P.” means meltingpoint, “r.m.” means reaction mixture;

Microwave assisted reactions were performed in a single-mode reactor:Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimodereactor: MicroSYNTH Labstation (Milestone, Inc.).

¹H NMR spectra were recorded on a Bruker DPX-400 and on a Bruker AV-500spectrometer with standard pulse sequences, operating at 400 MHz and 500MHz respectively, using CDCL₃ and C₆D₆ as solvents. Chemical shifts (δ)are reported in parts per million (ppm) downfield from tetramethylsilane(TMS), which was used as internal standard.

DESCRIPTION 1 4-Benzyloxy-1-butyl-1H-pyridin-2-one (D1)

1-Bromobutane (3.75 g, 27.33 mmol) and potassium carbonate (10.3 g,74.52 mmol) were added to a solution of 4-benzyloxy-1H-pyridin-2-one(5.0 g, 24.84 mmol) in CH₃CN (200 ml). The mixture was heated at refluxtemperature for 16 h. The r.m. was then filtered through diatomaceousearth and concentrated in vacuo. The crude residue was then trituratedwith diethyl ether to yield pure D1 (6.26 g, 98%) as a white solid.

DESCRIPTION 2 1-Butyl-4-hydroxy-1H-pyridin-2-one (D2)

A mixture of intermediate D1 (2.01 g, 7.83 mmol) and a catalytic amountof 10% palladium on activated carbon in ethanol (300 ml) was stirredunder a H₂ atmosphere for 2 h. The mixture was filtered throughdiatomaceous earth and the solvent was evaporated in vacuo to yieldintermediate D2 (1.3 g, 100%). The crude was used as such in the nextreaction step without further purification.

DESCRIPTION 3 1-Butyl-3-chloro-4-hydroxy-1H-pyridin-2-one (D3)

N-chlorosuccinimide (1.6 g, 11.96 mmol) was added to a solution ofintermediate D2 (2.0 g, 11.96 mmol) in DMF (30 ml). The mixture wasstirred overnight at r.t. and was then concentrated in vacuo. The crudeproduct was purified by column chromatography (silica gel; 0-5% MeOH/DCMas eluent) to yield intermediate D3 (2.0 g, 83%).

DESCRIPTION 4 Trifluoro-methanesulfonic acid1-butyl-3-chloro-2-oxo-1,2-dihydropyridin-4-yl ester (D4)

Pyridine (1.60 ml, 19.8 mmol) was added to a cooled solution (−78° C.)of intermediate D3 (2.0 g, 9.92 mmol) in DCM (80 ml). The resultingsolution was stirred for 10 min. after which trifluoromethanesulfonicanhydride (1.90 ml, 10.9 mmol) was added. The resulting solution wasstirred at −78° C. for 3 h. Subsequently, the mixture was warmed to r.t.and was then quenched by the addition of aqueous saturated ammoniumchloride. This mixture was diluted with H₂O and extracted with DCM. Theseparated organic layer was dried (Na₂SO₄), filtered and the solvent wasevaporated in vacuo. Yield: 3.31 g of intermediate D4 (100%) as a crudethat was used in the next reaction step without further purification.

DESCRIPTION 5 Trifluoro-methanesulfonic acid3-chloro-1-3-methyl-butyl)-2-oxo-1,2-dihydro-pyridin-4-yl ester (D5)

Intermediate D5 was prepared following the same procedure implementedfor the synthesis of D4, but 1-isopentyl-4-hydroxy-1H-pyridin-2-one wasused as the starting material. 1-Isopentyl-4-hydroxy-1H-pyridin-2-onewas prepared by the same method used for the synthesis of intermediateD2, by reaction of 4-benzyloxy-1H-pyridin-2-one with isopentylbromide.

DESCRIPTION 6 Trifluoro-methanesulfonic acid3-chloro-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyridin-4-yl ester (D6)

Intermediate D6 was prepared following the same procedure implementedfor the synthesis of D4, using as starting material1-cyclopropylmethyl-4-hydroxy-1H-pyridin-2-one which was prepared by thesame method used for the synthesis of intermediate D2, by reaction of4-benzyloxy-1H-pyridin-2-one with cyclopropylmethyl-bromide.

DESCRIPTION 7 2-(Tetrahydro-pyran-4-ylamino)-phenol (D7)

A mixture of 2-aminophenol (1 g, 9.164 mmol), tetrahydropyran-4-one(1.099 ml, 11.913 mmol), and sodium triacetoxy-borohydride (0.71 g, 3.42mmol) in DCE (50 ml) was stirred at r.t. for 16 h. The crude wasfiltered over diatomaceous earth, washed with DCM and the filtrate wasevaporated in vacuo to yield D7 (0.69 g) that was used as such in thenext reaction step without further purification.

DESCRIPTION 8 2-(1,4-Dioxa-spiro[4.5]dec-8-ylamino)-phenol (D8)

A mixture of 2-aminophenol (2 g, 18.327 mmol), 1,4-cyclohexanedionemonoethyleneketal (3.721 g, 23.825 mmol), and sodiumtriacetoxy-borohydride (5.826 g, 27.491 mmol) in DCE (20 ml) and aceticacid (0.2 ml) was stirred at r.t. for 3 h. The r.m. was diluted with DCMand washed with NaHCO₃ aqueous saturated solution, dried (Na₂SO₄) andthe solvent was evaporated in vacuo. The solid residue thus obtained wastriturated with diisopropyl ether to yield D8 (3.78 g) as a white solid.

DESCRIPTION 9 5-Bromo-2-(tetrahydro-pyran-4-ylamino)-phenol (D9)

A solution of intermediate D7 (0.66 g, 3.415 mmol) andN-bromosuccinimide (0.669 g, 3.757 mmol) in DMF (10 ml) was stirred atr.t. for 1 h. Subsequently, the r.m. was washed with an aqueoussaturated NaHCO₃ solution. The organic layer was separated, dried(Na₂SO₄), filtered and the solvent evaporated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM/EtOAc 8:2as eluent). The desired fractions were collected and evaporated in vacuoto yield D9 (0.433 g, 46.6%) as a reddish solid.

DESCRIPTION 10 5-Bromo-2-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-phenol(D10)

A solution of intermediate D8 (1 g, 4.011 mmol) and N-bromosuccinimide(0.785 g, 4.412 mmol) in DMF (15 ml) was stirred at r.t. for 1 h.Subsequently, the r.m. was washed with an aqueous saturated NaHCO₃solution. The organic layer was separated, dried (Na₂SO₄), filtered andthe solvent was evaporated in vacuo. The crude product was purified bycolumn chromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desiredfractions were collected and evaporated in vacuo to yield D10 (0.433 g,32.89%) as a reddish solid.

DESCRIPTION 117-Bromo-4-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (D11)

A mixture of intermediate D9 (0.433 g, 1.591 mmol), 1,2-dibromoethane(0.411 ml, 4.773 mmol and potassium carbonate (1.099 g, 7.955 mmol) inDMF (10 ml) was heated at 180° C. for 15 min. under microwaveirradiation. After cooling to r.t. the r.m. was filtered throughdiatomaceous earth. The filtrate was evaporated in vacuo. The cruderesidue was purified by column chromatography (silica gel; DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield a colorless oil that crystallized to yield D11 (0.267 g, 56%) as awhite solid.

M.P.: 66.2° C.

DESCRIPTION 127-Bromo-4-(1,4-dioxa-spiro[4.5]dec-8-yl)-3,4-dihydro-2H-benzol-[1,4]oxazine(D12)

A mixture of intermediate D10 (0.433 g, 1.319 mmol), 1,2-dibromoethane(0.341 ml, 3.958 mmol and potassium carbonate (0.912 g, 6.596 mmol) inDMF (10 ml) was heated at 180° C. for 15 min. under microwaveirradiation. After cooling to r.t. the r.m. was filtered throughdiatomaceous earth. The filtrate was evaporated in vacuo. The cruderesidue was purified by column chromatography (silica gel; DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield a colorless oil that crystallized to yield D12 (0.271 g, 58%).

DESCRIPTION 134(7-Bromo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-cyclohexanone (D13)

A mixture of intermediate D12 (0.250 g, 0.706 mmol), p-toluenesulfonicacid (13.424 mg, 0.0706 mmol) in H₂O (5 ml) and acetone (2.5 ml) washeated at 100° C. for 15 min. under microwave irradiation. After coolingto r.t. the r.m. was diluted with DCM and washed with a saturatedaqueous NaHCO₃ solution, dried (Na₂SO₄) and evaporated in vacuo. Ther.m. was purified by column chromatography (silica gel; DCM as eluent).The desired fractions were collected and evaporated in vacuo to yieldD13 (0.172 g, 78%) as a white solid.

M.P.: 101.8° C.

DESCRIPTION 14trans-4-(7-Bromo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-cyclohexanol (D14)

A mixture of intermediate D13 (0.170 g, 0.548 mmol) and sodiumborohydride (62.198 mg, 1.644 mmol) in MeOH (10 ml) was stirred at r.t.for 2 h. Then, the resulting mixture was quenched with an aqueoussaturated ammonium chloride solution and extracted with DCM. Theseparated organic layer was collected, dried (Na₂SO₄), filtered andevaporated in vacuo. The residue thus obtained was purified by circularchromatography (silica gel; DCM as eluent). The desired fractions werecollected and evaporated in vacuo to yield D14 (0.150 g, 88%) as a whitesolid (trans).

DESCRIPTION 15trans-4-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-cyclohexanol(D15)

Bis(pinacolato)diboron (0.171 g, 0.673 mmol) and potassium acetate(0.141 g, 1.441 mmol) were added to a solution of intermediate D14(0.150 g, 0.48 mmol) in dioxane (12 ml). The mixture was degassed andthen[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-complexwith DCM (1:1) (0.021 g, 0.0288 mmol) was added. The r.m. was heatedovernight at 95° C. in a sealed tube. After cooling to r.t., the r.m.was filtered through diatomaceous earth. The filtrate was evaporated invacuo. The crude residue was purified by column chromatography (silicagel; DCM/EtOAc gradient from 100:0 to 90:10 as eluent). The desiredfractions were collected and evaporated in vacuo to afford a colourlessoily residue that crystallized to yield D15 (0.123 g, 71%) as a whitesolid (trans).

DESCRIPTION 164-(Tetrahydro-pyran-4-yl)-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[1,4]oxazine(D16)

Bis(pinacolato)diboron (315.956 mg, 1.244 mmol) and potassium acetate(261.659 mg, 2.666 mmol) were added to a solution of intermediate D11(265 mg, 0.889 mmol) in dioxane (12 ml). The mixture was degassed andthen[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-complexwith DCM (1:1) (39.125 mg, 0.0533 mmol) was added. The r.m. was heatedovernight at 95° C. in a sealed tube. After cooling to r.t., the r.m.was filtered through diatomaceous earth. The filtrate was evaporated invacuo. The crude residue was purified by column chromatography (silicagel; DCM as eluent). The desired fractions were collected and thesolvent was evaporated in vacuo to yield a colorless oily residue thatcrystallized to yield D16 (0.61 g, 19.88%) as a white solid.

DESCRIPTION 17 5-Bromo-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-indole (D17)

A mixture of 5-bromoindole (8.472 g, 43.216 mmol, toluene-4-sulfonicacid 1,4-dioxa-spiro[4.5]dec-8-yl ester (13.5 g, 43.216 mmol) (preparedaccording to the procedure described in Journal of the Chemical Society,Perkin Transactions 1 (2002), (20), 2251-2255) and powdered potassiumhydroxide (13.239 g, 235.958 mmol) in DMSO (300 ml) was stirred at 80°C. for 6 h. Subsequently, the mixture was poured into ice water. Theresulting aqueous mixture was extracted with diethylether (3×), dried(Na₂SO₄), filtered and the solvent was evaporated in vacuo. The cruderesidue thus obtained was purified by column chromatography (silica gel;0-10% DCM/heptane 1:1 as eluent). The desired fractions were collectedand evaporated in vacuo to yield D17 (2.897 g, 19.93%) as a white solid.

DESCRIPTION 18 4-(5-Bromo-indol-1-yl)-cyclohexanone (D18)

A mixture of intermediate D17 (24 g, 71.38 mmol) and p-toluenesulfonicacid (0.679 mg, 3.569 mmol) in water (72 ml) and acetone (168 ml) washeated for 15 min. at 100° C. under microwave irradiation. After coolingto r.t., the r.m. was diluted with DCM and washed with a saturatedaqueous NaHCO₃ solution, dried (Na₂SO₄), filtered and the solvent wasevaporated in vacuo. The residue thus obtained was triturated withdiethyl ether (100 ml)/acetone (30 ml). The solid was filtered off andthe filtrate was evaporated in vacuo to yield D18 (18.13 g, 73%) as ayellow oil.

DESCRIPTION 19 4-(5-Bromo-indol-1-yl)-cyclohexanol (D19)

Sodium borohydride (62.198 mg, 1.644 mmol) was added to a stirredmixture at 0° C. of intermediate D18 (2.074 g, 7.098 mmol) in MeOH (50ml). The resulting r.m. was warmed to r.t. and stirred for 1 h.Subsequently, the mixture was concentrated in vacuo and the residue thusobtained was dissolved in DCM. This solutions was washed with an aqueoussaturated ammonium chloride solution. The organic layer was isolated,dried (Na₂SO₄), filtered and the solvent was evaporated in vacuo. Theresidue was purified by chromatography (silica gel; EtOAc:Heptanegradient from 0:100 to 30:70 as eluent). The desired fractions werecollected and the solvent was evaporated in vacuo to yield trans-D19(1.809 g, 86.6%) and cis-D19 (0.110 g, 5.27%).

DESCRIPTION 20 (Trans)trans-4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-indol-1-yl]-cyclohexanol(trans-D20)

Bis(pinacolato)diboron (0.829 g, 3.263 mmol) and potassium acetate(0.300 g, 3.059 mmol) were added to a solution of intermediate trans-D19(0.300 g, 1.02 mmol) in dioxane (12 ml) and DMF (2 ml). The mixture wasdegassed and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(ID-complexwith DCM (1:1) (0.0374 g, 0.051 mmol) was added. The r.m. was heated for1 h. at 160° C. under microwave irradiation. After cooling to r.t., ther.m. was filtered through diatomaceous earth. The filtrate wasevaporated in vacuo. The residue was purified by column chromatography(silica gel; eluent: DCM/EtOAc gradient from 100:0 to 60:40). Thedesired fractions were collected and the solvent was evaporated in vacuoto yield trans-D20 (0.260 g, 74.6%).

DESCRIPTION 20 (Cis)cis-4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-indol-1-yl]-cyclohexanol(cis-D20)

Bis(pinacolato)diboron (0.265 g, 1.042 mmol) and potassium acetate(0.219 g, 2.233 mmol) were added to a solution of intermediate cis-D19(0.219 g, 0.744 mmol) in dioxane (4 ml). The mixture was degassed andthen[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-complexwith DCM (1:1) (0.033 g, 0.045 mmol) was added. The r.m. was heated for2 h. at 95° C. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth. The filtrate was evaporated in vacuo. The residuewas purified by column chromatography (silica gel; heptane/EtOAcgradient from 100:0 to 80:20 as eluent). The desired fractions werecollected and the solvent was evaporated in vacuo to yield intermediatecis-D20 (0.213 g, 83.8%).

M.P.: 187.7° C.

DESCRIPTION 21 4-(5-Bromo-indol-1-yl)-1-methyl-cyclohexanol (D21)

A methylmagnesium bromide solution (1.4 M solution in toluene/THF)(3.667 ml, 5.134 mmol) was added dropwise to a cooled solution (at 0°C.) of intermediate D18 (0.5 g, 1.711 mmol) in THF (20 ml) under N₂atmosphere. The resulting r.m. was stirred at r.t. for 4 h. Aftercooling in an ice bath, the mixture was carefully quenched with asaturated aqueous solution of ammonium chloride, and was subsequentlyextracted with DCM. The separated organic fraction was dried (Na₂SO₄),filtered and the solvent was evaporated in vacuo. The crude residue waspurified by column chromatography (silica gel; 0-30% EtOAc/heptane aseluent). The desired fractions were collected and the solvent wasevaporated in vacuo to yield cis-D21 (0.096 g, 18.2%) and trans-D21(0.12 g, 22.7%).

M.P. cis-D21: 111° C.

M.P. trans-D21: 95.9° C.

DESCRIPTION 22 (Cis)cis-1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indol-1-yl]-cyclohexanol(cis-D22)

Bis(pinacolato)diboron (0.111 g, 0.436 mmol) and potassium acetate(0.0917 g, 0.934 mmol) were added to a solution of intermediate cis-D21(0.096 g, 0.311 mmol) in dioxane (4 ml). The mixture was degassed andthen[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-complexwith DCM (1:1) (0.0137 g, 0.0187 mmol) was added. The r.m. was heated at100° C. for 1.5 h. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth. The filtrate was evaporated in vacuo. The residuewas purified by column chromatography (silica gel; heptane/EtOAcgradient from 100:0 to 80:20 as eluent). The desired fractions werecollected and the solvent was evaporated in vacuo to yield cis-D22(0.074 g, 66.87%).

DESCRIPTION 22 (Trans)trans-1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indol-1-yl]-cyclohexanol(trans-D22)

Bis(pinacolato)diboron (0.130 g, 0.513 mmol) and potassium acetate(0.108 g, 1.1 mmol) were added to a solution of intermediate cis-D21(0.113 g, 0.367 mmol) in dioxane (5 ml). The mixture was degassed andthen[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)-complexwith DCM (1:1) (0.0161 g, 0.022 mmol) was added. The r.m. was heated at100° C. for 2.5 h. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth. The filtrate was evaporated in vacuo. The residuewas purified by column chromatography (silica gel; heptane/EtOAcgradient from 100:0 to 80:20 as eluent). The desired fractions werecollected and evaporated in vacuo to yield trans-D22 (0.096 g, 74%).

DESCRIPTION 231-Butyl-3-chloro-4-[4-(4-oxo-cyclohexyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-1H-pyridin-2-one(D23)

A mixture of intermediate D15 (0.15 g, 0.418 mmol), intermediate D4(0.139 g, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0241g, 0.0209 mmol) and an aqueous saturated NaHCO₃ solution (1 ml) indioxane (4 ml), was heated at 150° C. for 10 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was washedwith water and then with brine. The organic fraction was dried (Na₂SO₄),filtered and the solvent was evaporated in vacuo. The crude residue waspurified by column chromatography (silica gel; 0-10% EtOAc/DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield D23 (0.027 g, 15.59%).

EXAMPLE 11-Butyl-3-chloro-4-[4-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-1H-pyridin-2-one(E1);

A mixture of intermediate D16 (0.2 g, 0.348 mmol), intermediate D4(0.116 g, 0.348 mmol), tetrakis(triphenylphosphine)palladium(0) (0.021g, 0.0174 mmol) and an aqueous saturated NaHCO₃ solution (1 ml) indioxane (4 ml) was heated at 150° C. for 10 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was washedfirst with water and subsequently with brine. The organic fraction wasdried (Na₂SO₄), filtered and the solvent was evaporated in vacuo. Thecrude residue was purified by column chromatography (silica gel; 0-10%EtOAc/DCM as eluent) followed by reversed phase HPLC on (C18 XBridge19×100). A gradient was applied from 80% NH₄CO₃H pH 9, and 20% CH₃CN to0% NH₄CO₃H pH 9 and 100% CH₃CN). The desired fractions were collectedand evaporated in vacuo to yield E1 (0.059 g, 41%) as a yellow solid.

M.P.: 140.7° C. 1H NMR (400 MHz, CDCl₃) δ ppm 0.97 (t, J=7.4 Hz, 3 H),1.34-1.46 (m, 2 H), 1.71-1.91 (m, 6 H), 3.31-3.38 (m, 2 H), 3.53 (td,J=11.7, 2.0 Hz, 2 H), 3.83-3.94 (m, 1 H), 3.99 (t, J=7.4 Hz, 2 H), 4.11(dd, J=11.3, 4.2 Hz, 2 H), 4.22-4.29 (m, 2 H), 6.19 (d, J=7.2 Hz, 1 H),6.80 (d, J=8.8 Hz, 1 H), 7.00 (d, J=2.3 Hz, 1 H), 7.06 (dd, J=8.6, 2.1Hz, 1 H), 7.17 (d, J=6.9 Hz, 1 H).

Compound E9 was prepared in analogy to the procedure described forcompound E1.

EXAMPLE 2trans-1-Butyl-3-chloro-4-[4-(4-hydroxy-cyclohexyl)-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl]-1H-pyridin-2-one(E2);

Sodium borohydride (2.507 mg, 0.0663 mmol) was added to a stirredmixture of intermediate D23 (0.025 g, 0.0603 mmol) in MeOH (2 ml) atr.t. The resulting r.m. was warmed to r.t. and stirred for 1 h.Subsequently, the mixture was washed with an aqueous saturated NaHCO₃solution and extracted with DCM. The separated organic layer wascollected, dried (Na₂SO₄), filtered and the solvent was evaporated invacuo. The residue was triturated with DIPE to yield E2 (20 mg) as awhite solid.

M.P.: 178° C. ¹ H NMR (400 MHz, C₆D₆) δ ppm 0.84 (t, J=7.3 Hz, 3 H),1.00-1.12 (m, 2 H), 1.10-1.20 (m, 2 H), 1.20-1.32 (m, 2 H), 1.42 (br.s., 1 H), 1.48-1.58 (m, 4 H), 1.81-1.92 (m, 2 H), 2.68-2.78 (m, 2 H),3.26-3.35 (m, 1 H), 3.35-3.45 (m, 1 H), 3.61 (t, J=7.4 Hz, 2 H),3.85-3.91 (m, 2 H), 5.96 (d, J=6.9 Hz, 1 H), 6.28 (d, J=6.9 Hz, 1 H),6.69 (d, J=8.8 Hz, 1 H), 7.36 (dd, J=8.4, 2.2 Hz, 1 H), 7.43 (d, J=2.1Hz, 1 H).

EXAMPLE 3trans-1-Butyl-3-chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one(E3);

A mixture of intermediate trans-D20 (1 g, 2.93 mmol), intermediate D4(0.815 g, 2.442 mmol), tetrakis(triphenylphosphine)palladium(0) (0.141g, 0.122 mmol) and an aqueous saturated NaHCO₃ solution (4 ml) indioxane (12 ml) was heated at 150° C. for 7 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was firstwashed with water and then with brine. The organic fraction was dried(Na₂SO₄), filtered and the solvent was evaporated in vacuo. The cruderesidue was purified by column chromatography (silica gel; 0-10%heptane/EtOAc as eluent). The desired fractions were collected andevaporated in vacuo. The residue was triturated with diethyl ether. Thewhite precipitate obtained was filtered off and dried in vacuo to yieldE3 (0.506 g, 52%) as a white solid.

M.P.: 191.1° C. ¹H NMR (500 MHz, CDCl₃) δ ppm 0.99 (t, J=7.4 Hz, 3 H),1.37-1.48 (m, 2 H), 1.53-1.66 (m, 3 H), 1.77-1.85 (m, 2 H), 1.82-1.93(m, 2 H), 2.19 (br d, J=12.4 Hz, 4 H), 3.74-3.88 (m, 1 H), 4.03 (t,J=7.4 Hz, 2 H), 4.21-4.36 (m, 1 H), 6.29 (d, J=6.9 Hz, 1 H), 6.57 (d,J=3.2 Hz, 1 H), 7.22 (d, J=6.9 Hz, 1 H), 7.24 (d, J=3.2 Hz, 1 H), 7.35(dd, J=8.5, 1.6 Hz, 1 H), 7.44 (d, J=8.4 Hz, 1 H), 7.75 (d, J=1.4 Hz, 1H).

EXAMPLE 4cis-1-Butyl-3-chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one(E4);

A mixture of intermediate cis-D20 (0.144 g, 0.422 mmol), intermediate D4(0.117 g, 0.352 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020g, 0.0176 mmol) and an aqueous saturated NaHCO₃ solution (1 ml) indioxane (3 ml) was heated at 150° C. for 7 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was firstwashed with water and subsequently with brine. The organic fraction wasdried (Na₂SO₄), filtered and the solvent was evaporated in vacuo. Thecrude residue was purified by column chromatography (silica gel;heptane/EtOAc from 100:0 to 30:70 as eluent). The desired fractions werecollected and evaporated in vacuo. The residue thus obtained wastriturated with DIPE. The white precipitate obtained was filtered offand dried in vacuo to yield E4 (0.077 g, 54%) as a white solid.

M.P.: 280.7° C. ¹H NMR, (500 MHz, CDCl₃) δ ppm 0.99 (t, J=7.4 Hz, 3 H),1.37 (br. s., 1 H), 1.38-1.49 (m, 2 H), 1.70-1.88 (m, 4 H), 1.95 (br d,J=11.9 Hz, 2 H), 2.02 (br d, J=14.7 Hz, 2 H), 2.26 (qd, J=12.7, 2.9 Hz,2 H), 4.03 (t, J=7.2 Hz, 2 H), 4.21 (br. s., 1 H), 4.24-4.35 (m, 1 H),6.30 (d, J=6.9 Hz, 1 H), 6.58 (d, J=2.9 Hz, 1 H), 7.22 (d, J=7.2 Hz, 1H), 7.30-7.39 (m, 2 H), 7.45 (d, J=8.7 Hz, 1 H), 7.75 (br. s., 1 H).

EXAMPLE 5trans-1-Butyl-3-chloro-4-[1-(4-hydroxy-4-methyl-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one(E5);

A mixture of intermediate trans-D22 (0.0964 g, 0.271 mmol), D4 (0.082 g,0.247 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.0176mmol) and a saturated aqueous NaHCO₃ solution (1 ml) in dioxane (3 ml)was heated at 150° C. for 7 min. under microwave irradiation. Aftercooling to r.t., the r.m. was filtered through diatomaceous earth,treated with EtOAc and the organic layer was washed with water andbrine. The organic fraction was dried (Na₂SO₄), filtered and the solventwas evaporated in vacuo. The crude residue was purified by columnchromatography (silica gel; heptane/EtOAc from 100:0 to 30:70 aseluent). The desired fractions were collected and the solvent wasevaporated in vacuo. The residue thus obtained was triturated withdiethyl ether. The white precipitate obtained was filtered off and driedin vacuo to yield E5 (0.545 g, 53.5%) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ ppm 0.99 (t, J=7.2 Hz, 3 H) 1.13 (s, 1 H) 1.35 (s, 3 H)1.38-1.47 (m, 2 H) 1.68 (td, J=13.7, 3.8 Hz, 2 H) 1.78-1.84 (m, 2 H)1.87 (br d, J=13.0 Hz, 2 H) 1.97 (br d, J=12.4 Hz, 2 H) 2.23 (qd,J=12.8, 3.5 Hz, 2 H) 4.02 (t, J=7.4 Hz, 2 H) 4.24 (tt, J=12.1, 3.7 Hz, 1H) 6.29 (d, J=6.9 Hz, 1 H) 6.57 (d, J=2.9 Hz, 1 H) 7.22 (d, J=7.2 Hz, 1H) 7.31-7.37 (m, 2 H) 7.44 (d, J=8.7 Hz, 1 H) 7.75 (d, J=0.9 Hz, 1 H).

EXAMPLE 6cis-1-Butyl-3-chloro-4-[1-(4-hydroxy-4-methyl-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one(E6);

A mixture of intermediate cis-D22 (0.074 g, 0.208 mmol), intermediate D4(0.063 g, 0.189 mmol), tetrakis(triphenylphosphine)palladium(0) (0.011g, 0.0095 mmol) and a saturated aqueous NaHCO₃ solution (1 ml) indioxane (3 ml) was heated at 150° C. for 7 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was washedwith water and brine. The organic fraction was dried (Na₂SO₄), filteredand the solvent was evaporated in vacuo. The crude residue was purifiedby column chromatography (silica gel; heptane/EtOAc from 100:0 to 30:70as eluent). The desired fractions were collected and evaporated invacuo. The residue thus obtained was triturated with diethyl ether. Thewhite precipitate obtained was filtered off and dried in vacuo to yieldE5 (0.54 g, 69.5%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.99(t, J=7.4 Hz, 3 H), 1.36-1.49 (m, 3 H), 1.43 (s, 3 H), 1.72-1.86 (m, 4H), 1.86-2.00 (m, 4 H), 2.07-2.23 (m, 2 H), 4.03 (t, J=7.3 Hz, 2 H),4.25-4.40 (m, 1 H), 6.29 (d, J=6.9 Hz, 1 H), 6.58 (d, J=3.2 Hz, 1 H),7.22 (d, J=7.2 Hz, 1 H), 7.27 (d, J=3.5 Hz, 1 H), 7.35 (dd, J=8.6, 1.Hz, 1 H), 7.43 (d, J=8.8 Hz, 1 H), 7.75 (d, J=1.2 Hz, 1 H).

EXAMPLE 7trans-3-Chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1-(3-methyl-butyl)-1H-pyridin-2-one(E7);

A mixture of intermediate trans-D20 (0.294 g, 0.863 mmol), intermediateD5 (0.25 g, 0.719 mmol), tetrakis(triphenylphosphine)palladium(0)(0.0415 g, 0.0359 mmol) and an aqueous saturated NaHCO₃ solution (2 ml)in dioxane (6 ml) was heated at 150° C. for 7 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was washedwith water and brine. The organic fraction was dried (Na₂SO₄), filteredand the solvent was evaporated in vacuo. The crude residue was purifiedby column chromatography (silica gel; 0-20% MeOH/DCM as eluent). Thedesired fractions were collected and the solvent was evaporated invacuo. The residue was triturated with diethyl ether. The whiteprecipitate was filtered off and dried in vacuo. Yield: 0.175 g ofcompound E7 (59%) as a white solid.

M.P. 182.3° C. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.00 (d, J=6.0 Hz, 6 H),1.52-1.65 (m, 3 H), 1.66-1.77 (m, 3 H), 1.78-1.96 (m, 2 H), 2.20 (br d,J=11.1 Hz, 4 H), 3.71-3.89 (m, 1 H), 3.96-4.11 (m, 2 H), 4.21-4.37 (m, 1H), 6.29 (d, J=6.9 Hz, 1 H), 6.57 (d, J=3.2 Hz, 1 H), 7.20-7.25 (m, 2H), 7.34 (dd, J=8.5, 1.4 Hz, 1 H), 7.43 (d, J=8.6 Hz, 1 H), 7.70-7.78(m, 1 H).

EXAMPLE 8trans-3-Chloro-1-cyclopropylmethyl-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one(E8);

A mixture of intermediate trans-D20 (0.308 g, 0.904 mmol), intermediateD6 (0.250 g, 0.754 mmol), tetrakis(triphenylphosphine)palladium(0)(0.0435 g, 0.0377 mmol) and a saturated aqueous NaHCO₃ solution (2 ml)in dioxane (6 ml) was heated at 150° C. for 7 min. under microwaveirradiation. After cooling to r.t., the r.m. was filtered throughdiatomaceous earth, treated with EtOAc and the organic layer was washedwith water and brine. The organic fraction was dried (Na₂SO₄), filteredand the solvent was evaporated in vacuo. The crude residue was purifiedby column chromatography (silica gel; 0-20% MeOH/DCM as eluent). Thedesired fractions were collected and evaporated in vacuo. The residuewas triturated with diethyl ether. The white precipitate obtained wasfiltered off and dried in vacuo to yield E8 (0.506 g, 52%) as a whitesolid.

M.P.=209.4° C. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.39-0.50 (m, 2 H),0.59-0.73 (m, 2 H), 1.29-1.38 (m, 1 H), 1.48-1.70 (m, 3 H), 1.77-1.97(m, 2 H), 2.20 (br d, J=11.1 Hz, 4 H), 3.76-3.87 (m, 1 H), 3.90 (d,J=7.2 Hz, 2 H), 4.20-4.38 (m, 1 H), 6.32 (d, J=7.2 Hz, 1 H), 6.58 (d,J=3.2 Hz, 1 H), 7.24 (d, J=3.5 Hz, 1 H), 7.32-7.38 (m, 2 H), 7.44 (d,J=8.8 Hz, 1 H), 7.76 (d, J=0.9 Hz, 1 H).

Physico-Chemical Data

LCMS—General Procedure

The HPLC measurement was performed using a HP 1100 from AgilentTechnologies comprising a pump (quaternary or binary) with degasser, anautosampler, a column oven, a diode-array detector (DAD) and a column asspecified in the respective methods below. Flow from the column wassplit to a MS spectrometer. The MS detector was configured with eitheran electrospray ionization source or an ESCI dual ionization source(electrospray combined with atmospheric pressure chemical ionization).Nitrogen was used as the nebulizer gas. The source temperature wasmaintained at 140° C. Data acquisition was performed withMassLynx-Openlynx software.

Method 1: This Method was Used for Example E3 and E9

In addition to the general procedure: Reversed phase HPLC was carriedout on an XDB-C18 cartridge (1.8 μm, 2.1×30 mm) from Agilent, at 60° C.with a flow rate of 1 ml/min, at 60° C. The gradient conditions usedare: 90% A (0.5 g/l ammonium acetate solution), 5% B (CH₃CN), 5% C(MeOH) to 50% B and 50% C in 6.5 min., to 100% B at 7 min. andequilibrated to initial conditions at 7.5 min. until 9.0 min. Injectionvolume 2 μl. High-resolution mass spectra (Time of Flight, TOF) wereacquired by scanning from 100 to 750 in 0.5 s. using a dwell time of 0.3s (E3) or 0.1 s (E9). The capillary needle voltage was 2.5 kV forpositive ionization mode and 2.9 kV for negative ionization mode. Thecone voltage was 20 V for both positive and negative ionization modes.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Method 2: This Method was Used for Example E1, E2,E7 and E8

In addition to the general procedure: Reversed phase HPLC was carriedout on a BEH-C18 column (1.7 μm, 2.1×50 mm) from Waters, with a flowrate of 0.8 ml/min, at 60° C. without split to the MS detector. Thegradient conditions used are: 95% A (0.5 g/l ammonium acetatesolution+5% CH₃CN), 5% B (mixture of CH₃CN/MeOH, 1/1), to 20% A, 80% Bin 4.9 min., to 100% B in 5.3 min., kept till 5.8 min. and equilibratedto initial conditions at 6.0 min. until 7.0 min. Injection volume 0.5μl. Low-resolution mass spectra (SQD detector; quadrupole) were acquiredby scanning from 100 to 1000 in 0.1 s. using an inter-channel delay of0.08 s. The capillary needle voltage was 3 kV. The cone voltage was 20 Vfor positive ionization mode and 30 V for negative ionization mode.

Method 3: This Method was Used for Example E4

In addition to the general procedure: Reversed phase HPLC was carriedout on a Sunfire-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. The gradient conditions used are: 95% A(0.5 g/l ammonium acetate solution+5% of CH₃CN), 2.5% B (CH₃CN), 2.5% C(MeOH) to 50% B and 50% C in 6.5 minutes, kept till 7 min. andequilibrated to initial conditions at 7.3 min. until 9.0 min. Injectionvolume 2 μl. High-resolution mass spectra (Time of Flight, TOF) wereacquired by scanning from 100 to 750 in 0.5 s. using a dwell time of 0.3s. The capillary needle voltage was 2.5 kV for positive ionization modeand 2.9 kV for negative ionization mode. The cone voltage was 20 V forboth positive and negative ionization modes. Leucine-Enkephaline was thestandard substance used for the lock mass calibration.

Method 4: This Method was Used for Example E5 and E6

In addition to the general procedure: Reversed phase HPLC was carriedout on a Sunfire-C18 column (2.5 μm, 2.1×30 mm) from Waters, with a flowrate of 1.0 ml/min, at 60° C. The gradient conditions used are: 95% A(0.5 g/l ammonium acetate solution+5% CH₃CN), 5% B (mixture ofCH₃CN/MeOH, 1/1), to 100% B in 5.0 minutes, kept till 5.15 min. andequilibrated to initial conditions at 5.3 min. until 7.0 min. Injectionvolume 2 μl. Low-resolution mass spectra (Quadrupole, MSD) were acquiredin electrospray mode by scanning from 100 to 1000 in 0.99 s., step sizeof 0.30 and peak width of 0.10 min. The capillary needle voltage was 1.0kV and the fragmentor voltage was 70 V for both positive and negativeionization modes.

Melting Points

For a number of compounds, melting points were determined in opencapillary tubes on a Mettler FP62 apparatus. Melting points weremeasured with a temperature gradient of 3 or 10° C./min. Maximumtemperature was 300° C. The M.P. was read from a digital display andwere obtained with experimental uncertainties that are commonlyassociated with this analytical method.

Nuclear Magnetic Resonance (NMR)

¹H NMR spectra were recorded on a Bruker DPX-400 and on a Bruker AV-500spectrometer with standard pulse sequences, operating at 400 MHz and 500MHz respectively, using CDCL₃ and C₆D₆ as solvents. Chemical shifts (δ)are reported in parts per million (ppm) downfield from tetramethylsilane(TMS), which was used as internal standard.

Table 1 lists compounds of Formula (I) that were prepared according toone of the above Examples (Ex. No.). RT means retention time (inminutes).

TABLE 1

Ex. Melting RT No. R¹ X n Y Point (° C.) MH⁺ (min) E1

—CH₂CH₂O— 2 —O— 140.7 403 3.40 E2

—CH₂CH₂O— 2

178.0 417 3.17 E3

—CH═CH— 2

191.1 399 4.10 E4

—CH═CH— 2

280.7 399 4.40 E5

—CH═CH— 2

decomposed 413 3.63 E6

—CH═CH— 2

decomposed 413 3.98 E7

—CH═CH— 2

182.3 413 3.60 E8

—CH═CH— 2

209.4 397 3.05 E9

—CH═CH— 2 —O— n.d. 385 4.29 n.d.: not determinedPharmacological Examples

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of Formula (I) are present. Compounds ofFormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Thebehaviour of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to Formula (I), are shown in Table 4.

[³⁵S] GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein α subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can bedetermined. mGluR2 receptors are shown to be preferentially coupled toGαi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGluR2 receptors both inrecombinant cell lines and in tissues (Schaffhauser et al 2003,Pinkerton et al, 2004, Mutel et al (1998) Journal of Neurochemistry.71:2558-64; Schaffhauser et al (1998) Molecular Pharmacology 53:228-33).Here we describe the use of the [³⁵S]GTPγS binding assay using membranesfrom cells transfected with the human mGluR2 receptor and adapted fromSchaffhauser et al ((2003) Molecular Pharmacology 4:798-810) for thedetection of the positive allosteric modulation (PAM) properties of thecompounds of this invention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 hours, prior to washing in PBS (phosphate-bufferedsaline), and then collection by scraping in homogenisation buffer (50 mMTris-HCl buffer, pH 7.4, 4° C.). Cell lysates were homogenized briefly(15 s) using an ultra-turrax homogenizer. The homogenate was centrifugedat 23 500×g for 10 min. and the supernatant discarded. The pellet wasresuspended in 5 mM Tris-HCl, pH 7.4 and centrifuged again (30 000×g, 20min., 4° C.). The final pellet was resuspended in 50 mM HEPES, pH 7.4and stored at −80° C. in appropriate aliquots before use. Proteinconcentration was determined by the Bradford method (Bio-Rad, USA) withbovine serum albumin as standard.

[³⁵S] GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulatory activity of testcompounds in membranes containing human mGluR2 was performed usingfrozen membranes that were thawed and briefly homogenised prior topre-incubation in 96-well microplates (15 μg/assay well, 30 minutes, 30°C.) in assay buffer (50 mM HEPES pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 50 μMGDP, 10 μg/ml saponin) with increasing concentrations of positiveallosteric modulator (from 0.3 nM to 50 μM) and either a minimalpre-determined concentration of glutamate (PAM assay), or no addedglutamate. For the PAM assay, membranes were pre-incubated withglutamate at EC₂₅ concentration, i.e. a concentration that gives 25% ofthe maximal response glutamate, and is in accordance to published data(Pin et al. (1999) Eur. J. Pharmacol. 375:277-294). After addition of[³⁵S]GTPγS (0.1 nM, f.c.) to achieve a total reaction volume of 200 μl,microplates were shaken briefly and further incubated to allow[³⁵S]GTPγS incorporation on activation (30 minutes, 30° C.). Thereaction was stopped by rapid vacuum filtration over glass-fibre filterplates (Unifilter 96-well GF/B filter plates, Perkin-Elmer, DownersGrove, USA) microplate using a 96-well plate cell harvester (Filtermate,Perkin-Elmer, USA), and then by washing three times with 300 μl ofice-cold wash buffer (Na₂PO₄.2H₂O 10 mM, NaH₂PO₄.H₂O 10 mM, pH=7.4).Filters were then air-dried, and 40 μl of liquid scintillation cocktail(Microscint-O) was added to each well, and membrane-bound [³⁵S]GTPγS wasmeasured in a 96-well scintillation plate reader (Top-Count,Perkin-Elmer, USA). Non-specific [³⁵S]GTPγS binding is determined in thepresence of cold 10 μM GTP. Each curve was performed at least once usingduplicate sample per data point and at 11 concentrations.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention in the presence of added EC₂₅ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM), weregenerated using the Prism GraphPad software (Graph Pad Inc, San Diego,USA). The curves were fitted to a four-parameter logistic equation(Y=Bottom+(Top−Bottom)/(1+10^((Log EC₅₀−X)*Hill Slope) allowingdetermination of EC₅₀ values. The EC₅₀ is the concentration of acompound that causes a half-maximal potentiation of the glutamateresponse. This was calculated by subtracting the maximal responses ofglutamate in presence of a fully saturating concentration of a positiveallosteric modulator from the response of glutamate in absence of apositive allosteric modulator. The concentration producing thehalf-maximal effect was then calculated as EC₅₀.

TABLE 2 Pharmacological data for compounds according to the invention.Comp. No. GTPgS-hR2 PAM pEC₅₀ 1 6.23 2 n.d. 3 6.99 4 6.83 5 7.12 6 6.527 7.05 8 6.52 9 6.51 All compounds were tested in presence of mGluR2agonist, glutamate at a predetermined EC₂₅ concentration, to determinepositive allosteric modulation (GTPγS-PAM). Values shown are averages ofduplicate values of 11-concentration response curves, from at least oneexperiment. All tested compounds showed a pEC₅₀ (-logEC₅₀) value of morethan 5.0, from 6.23 (weak activity) to 7.05 (very high activity). Theerror of determination of a pEC₅₀ value for a single experiment isestimated to be about 0.3 log-units. n.d. = not determined

Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

The invention claimed is:
 1. A compound having the formula (I)

or a stereochemically isomeric form thereof, wherein R¹ is C₁₋₆alkyl; orC₁₋₃alkyl substituted with C₃₋₇cycloalkyl, halo, phenyl, or phenylsubstituted with halo, trifluoromethyl or trifluoromethoxy; R² is halo,trifluoromethyl, C₁₋₃alkyl or cyclopropyl; R³ is hydrogen, halo ortrifluoromethyl; n is 1 or 2; X is —CH₂CH₂—O—, —CH═CH—, or —CH₂CH₂—; Yis —O— or —CR⁴(OH)—; R⁴ is hydrogen or C₁₋₃ alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1 wherein R¹is C₁₋₆alkyl; or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl, phenyl, orphenyl substituted with halo, trifluoromethyl or trifluoromethoxy; R² ishalo, trifluoromethyl, C₁₋₃alkyl or cyclopropyl; R³ is hydrogen, halo ortrifluoromethyl; n is 1 or 2; X is —CH₂CH₂—O—, —CH═CH—, or —CH₂CH₂—; Yis —O— or —CR⁴(OH)—; R⁴ is hydrogen or C₁₋₃ alkyl; or a pharmaceuticallyacceptable salt thereof.
 3. The compound according to claim 1 wherein R¹is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or2-(cyclopropyl)-1-ethyl; R² is chloro, bromo, cyclopropyl ortrifluoromethyl; R³ is hydrogen or chloro or trifluoromethyl; n is 2; Xis —CH₂CH₂—O— or —CH═CH—; Y is —O— or —CR⁴(OH)—; R⁴ is hydrogen orC₁₋₃alkyl; or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1 wherein said compound istrans-1-Butyl-3-chloro-4-[1-(4-hydroxy-cyclohexyl)-1H-indol-5-yl]-1H-pyridin-2-one(E3), ortrans-1-Butyl-3-chloro-4-[1-(4-hydroxy-4-methyl-cylohexyl)-1H-indol-5-yl]-1H-pyridin-2-one (E5).
 5. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable carrier or excipient.
 6. A method oftreating, ameliorating, or controlling a central nervous system disorderin a human, comprising administering to the human in need thereof aneffective amount of a compound according to claim 1, wherein the centralnervous system disorder is selected from the group consisting of anxietydisorders, psychotic disorders selected from the group consisting ofschizophrenia, schizoaffective disorder and schizophreniform disorder,mood disorders, epilepsy or convulsive disorders, and dementia of theAlzheimer's type.
 7. The method according to claim 6, wherein thecentral nervous system disorder is an anxiety disorder, selected fromthe group consisting of agoraphobia, generalized anxiety disorder (GAD),obsessive-compulsive disorder (OCD), panic disorder, posttraumaticstress disorder (PTSD), social phobia and other phobias.
 8. The methodaccording to claim 6, wherein the central nervous system disorder is apsychotic disorder selected from the group consisting of schizophrenia,schizoaffective disorder, and schizophreniform disorder.
 9. The methodaccording to claim 6, wherein the central nervous system disorder is amood disorder selected from the group consisting of bipolar disorders (I& II), cyclothymic disorder, depression, dysthymic disorder, majordepressive disorder and substance-induced mood disorder.
 10. The methodaccording to claim 6, wherein the central nervous system disorder isepilepsy or a convulsive disorder selected from the group consisting ofgeneralized nonconvulsive epilepsy, generalized convulsive epilepsy,petit mal status epilepticus, grand mal status epilepticus, partialepilepsy with or without impairment of consciousness, infantile spasms,epilepsy partialis continua, and other forms of epilepsy.
 11. The methodof claim 6, comprising administering to the human in need thereof aneffective amount of a compound according to claim 1 and an orthostericagonist of mGluR2 as a combined preparation for simultaneous, separateor sequential administration to the patient.
 12. The method of claim 6,wherein the compound is administered as a pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier or excipient.